Thyroid cancer is the most common endocrine malignancy with an annual incidence of 21,000 in the U.S. 5- 10% of patients have advanced thyroid cancer that is unresponsive to standard therapy, and 1,500 patients die each year from this disease. There are Currently no effective therapies for patients with advanced thyroid cancer. Retinoid therapy (derivatives of vitamin A) is effective in some patients with leukemia, head & neck cancer, lung cancer and breast cancer. This therapy has shown some promise for patients with advanced thyroid cancer, but only 20-40% of patients responsd to retinoid treatment. We hypothesized that patients with advanced thyroid cancer would respond to retinoid therapy based on retinoic acid receptor (RAR a, b, gamma) and retinoid X receptor (RXR a, b, gamma) expression. While testing this hypothesis, we identified a unique pattern of expression of two receptors (RARb and RXRgamma) in thyroid cancer cell lines and tumor tissue. The expression of these receptors is associated with growth inhibition by synthetic retinoids, and this heterodimer (RARb /RXRgamma) may be critical in mediating the retinoid response. We have also shown that expression of another nuclear hormone receptor (PPARgamma) is associated with growth inhibition by thiazolidinediones (TZD), and may form a unique heterodimer with RXRgamma to mediate this response. Based on these preliminary results, we hypothesize that two unique heterodimer pathways are necessary and sufficient for response to retinoid and TZD treatment: RARb/RXRgamma, which mediates growth suppression and differentiation, and PPARgamma/RXRgamma, which mediates growth suppression and apoptosis. The goals of this proposal are to define the roles of the RXRgamma, RARb and PPARgamma nuclear hormone receptors in mediating response to retinoid and TZD therapy for advanced thyroid cancer through in vitro cell line models and in vivo mouse thyroid carcinoma models. We will also explore the role of leukemia inhibitory factor (identified by microarray analysis) as a direct mechanism through which the effects of retinoids and TZD mediate growth arrest in advanced thyroid carcinoma. Successful completion of these aims will provide a fundamental understanding of how retinoids and TZD affect cancer cell growth and differentiation, as well as identify molecular tools to design clinical studies that will be the basis of individualized therapy for patients with cancer.